Snoeck R, Andrei G, De Clercq E
Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Expert Opin Investig Drugs. 2000 Aug;9(8):1743-51. doi: 10.1517/13543784.9.8.1743.
Varicella-zoster virus (VZV), a member of the herpesvirus family, is responsible for both primary (varicella or chickenpox) as well as recurrent (zoster or shingles) infections. Acyclovir has been the mainstay for treating VZV infections in both immunocompetent and immunocompromised patients. Recently, newer anti-VZV drugs, i.e., valaciclovir (the oral prodrug form of acyclovir) and famciclovir (the oral prodrug form of penciclovir) have been developed and have enlarged the therapeutic options to treat VZV infections. Both acyclovir and penciclovir are dependent on the virus-encoded thymidine kinase (TK) for their intracellular activation. Although emergence of drug-resistant strains does not occur in immunocompetent patients, several reports have documented the isolation of drug-resistant VZV strains following long-term acyclovir therapy in immunocompromised patients. Mutations at the level of the TK are responsible for development of resistance to drugs that depend on the viral TK for their phosphorylation (i.e., acyclovir and penciclovir). Foscarnet, a direct inhibitor of the viral DNA polymerase, which does not require activation by the viral TK, is the drug of choice for the treatment of TK-deficient VZV mutants emerging under acyclovir therapy. Recently, emergence of foscarnet-resistant strains has also been reported. Both TK-deficient strains and foscarnet-resistant mutants are sensitive to the acyclic nucleoside phosphonate cidofovir, CDV, HPMPC, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine. This agent does not depend on the virus-encoded TK, but on cellular enzymes for its conversion to the diphosphoryl derivative, which then inhibits the viral DNA polymerase.
水痘带状疱疹病毒（VZV）是疱疹病毒家族的成员，可引起原发性感染（水痘）和复发性感染（带状疱疹）。阿昔洛韦一直是治疗免疫功能正常和免疫功能低下患者VZV感染的主要药物。最近，新型抗VZV药物，即伐昔洛韦（阿昔洛韦的口服前体药物形式）和泛昔洛韦（喷昔洛韦的口服前体药物形式）已被开发出来，扩大了治疗VZV感染的选择范围。阿昔洛韦和喷昔洛韦在细胞内的激活都依赖于病毒编码的胸苷激酶（TK）。虽然在免疫功能正常的患者中不会出现耐药菌株，但有几份报告记录了免疫功能低下患者长期接受阿昔洛韦治疗后分离出耐药VZV菌株。TK水平的突变导致对依赖病毒TK进行磷酸化的药物（即阿昔洛韦和喷昔洛韦）产生耐药性。膦甲酸钠是病毒DNA聚合酶的直接抑制剂，不需要病毒TK激活，是治疗阿昔洛韦治疗下出现的TK缺陷型VZV突变体的首选药物。最近，也有膦甲酸钠耐药菌株出现的报道。TK缺陷菌株和膦甲酸钠耐药突变体对无环核苷膦酸盐西多福韦（CDV、HPMPC、（S）-1-（3-羟基-2-膦酰甲氧基丙基）胞嘧啶）敏感。这种药物不依赖病毒编码的TK，而是依赖细胞酶将其转化为二磷酸衍生物，然后抑制病毒DNA聚合酶。
